What is the diagnosis and management for a sexually inactive man with multiple painless reddish lesions on his penis, without itching, exudates, or ulcerations?

Diagnosis: Penile Intraepithelial Neoplasia (Erythroplasia of Queyrat)

The most likely diagnosis is penile intraepithelial neoplasia (PeIN), specifically erythroplasia of Queyrat, and biopsy is mandatory before any treatment to distinguish in situ from invasive disease. 1

Why This Diagnosis Takes Priority

The clinical presentation of multiple painless reddish lesions on the penis in a sexually inactive man strongly suggests erythroplasia of Queyrat, which is a form of penile intraepithelial neoplasia (carcinoma in situ) that characteristically presents as shiny erythematous plaques on the mucosal surface of the inner prepuce and/or glans penis. 2

Key distinguishing features that point to this diagnosis:

• Painless reddish lesions match the classic presentation of erythroplasia of Queyrat, which appears as red plaques on mucosal surfaces 2
• Absence of exudates or ulcerations helps exclude infectious causes like candidal balanitis or syphilis 3
• No itching makes inflammatory dermatoses like lichen sclerosus less likely, though not impossible 2
• Sexual inactivity for one year reduces likelihood of acute sexually transmitted infections, though does not exclude HPV-related lesions which can have long latency periods 1

Mandatory Immediate Actions

Biopsy is absolutely required before initiating any treatment. 1 The European Society for Medical Oncology emphasizes that any persistent penile lesion must undergo biopsy to exclude neoplastic change, given the risk of progression to invasive squamous cell carcinoma. 1 Up to 20% of patients with presumed PeIN harbor invasive disease on histopathological examination. 2

During physical examination, document:

• Exact morphology of lesions (papillary, nodular, ulcerous, or flat) 1
• Color and boundaries of each lesion 1
• Size and location of all lesions 2
• Presence of any palpable inguinal lymph nodes 2

Additional mandatory testing:

• Syphilis serology to exclude secondary syphilis, which can present with annular plaques 1
• Consider HPV testing for risk stratification once biopsy confirms PeIN 1

Critical Differential Diagnoses to Exclude

While erythroplasia of Queyrat is most likely, you must systematically exclude:

1. Lichen sclerosus - typically presents with grayish-white discoloration rather than reddish lesions, though early disease can have erythematous components 2, 4. The absence of itching makes this less likely, as lichen sclerosus is usually pruritic. 2

2. Bowenoid papulosis - typically presents as raised papules rather than flat reddish lesions, usually in younger sexually active men with HPV exposure 2, 1. Has lower risk of progression to invasive cancer compared to erythroplasia of Queyrat. 2

3. Candidal balanitis - would typically present with exudates, satellite lesions, and pruritus 3. The absence of these features makes fungal infection unlikely.

4. Secondary syphilis - can present with annular plaques but these are typically more widespread and accompanied by systemic symptoms 1. Serology will definitively exclude this.

5. Penile tuberculosis - presents with painless nodules or ulcers that gradually enlarge 5. The multiple lesion pattern and absence of induration make this less likely, but consider if patient has risk factors or history of pulmonary TB.

Treatment Algorithm Based on Biopsy Results

If Biopsy Confirms PeIN (Erythroplasia of Queyrat):

Surgical options (preferred for definitive diagnosis and staging):

• Wide local excision provides complete histopathological staging and detects areas of invasion 2
• Circumcision if lesions are on prepuce 2
• Partial glans resurfacing for glans lesions 2
• Recurrence rates with surgical excision: 0-20% 2

Non-surgical alternatives (if surgery declined or not feasible):

• Topical imiquimod: Response rates 40-100%, recurrence rate 20% 2. No consensus on optimal schedule; tolerance can be problematic. 2
• 5-fluorouracil (5-FU): Response rates 48-74%, recurrence rate 11% 2
• Laser ablation (Nd:YAG or CO2): Response rates 52-100%, recurrence rates 7-48% 2

Critical caveat: Resection is superior to ablative or topical treatments because it provides histopathological confirmation and can detect invasive disease that is present in up to 20% of cases. 2

If Biopsy Shows Lichen Sclerosus:

• Apply clobetasol propionate 0.05% ointment once daily for 1-3 months 4
• Use emollient as soap substitute and barrier preparation 4
• For recurrence, repeat topical treatment course for 1-3 months 4
• Long-term maintenance may require 30-60g of clobetasol propionate 0.05% ointment annually 4

Follow-Up Protocol

If PeIN is confirmed, intensive surveillance is mandatory:

• Every 3-6 months for the first 2-3 years 1
• Then every 6-12 months thereafter 1
• 92% of recurrences occur within 5 years 1

Instruct patient to immediately report:

• Any persistent ulceration 2
• New growths 2
• Changes in existing lesions 2

If lichen sclerosus is confirmed:

• Follow-up at 3 months to assess treatment response 2
• Second visit at 6 months if response satisfactory 2
• Annual follow-up with primary care physician if using topical corticosteroids 2
• Long-term monitoring for squamous cell carcinoma risk 2

Common Pitfalls to Avoid

Never treat empirically without biopsy. 1 The consequences of missing invasive squamous cell carcinoma or delaying diagnosis of PeIN are severe, as erythroplasia of Queyrat has the highest risk among penile intraepithelial neoplasias of progressing to invasive cancer. 2

Do not assume sexual inactivity excludes HPV-related disease. HPV can have long latency periods, and erythroplasia of Queyrat is strongly associated with HPV exposure. 1

Do not rely on clinical appearance alone to distinguish between PeIN variants. Erythroplasia of Queyrat, Bowen's disease, and bowenoid papulosis are histologically indistinguishable and require biopsy for definitive diagnosis. 2

If topical treatments are used, treatment effects must be clinically assessed and biopsied if there is any doubt. Insufficient responses and recurrences may signify underlying invasive disease. 2